Organic Intermediates and Reaction Transformations
Organic Intermediates and Reaction Transformations
Organic Intermediates
Most organic reactions proceed via a reactive, short-lived intermediate species.
These intermediates typically have a carbon atom with a valency of 2 or 3.
Examples include carbocations, carbanions, free radicals, carbenes, and nitrenes.
Carbanions are unique among these intermediates as they possess a complete octet around the carbon atom.
Nitrenes are nitrogen analogs of carbenes, featuring charges and unpaired electrons on nitrogen atoms.
Carbocations
Carbocations are organic species with a positively charged carbon atom bonded to only six electrons.
The positively charged carbon is \text{sp}^2 hybridized.
The three sp^2 hybridized orbitals form bonds with three substituents, resulting in a planar configuration with bond angles of 120^o to minimize electron pair repulsion.
An empty p orbital is perpendicular to this plane.
Carbocations are highly reactive due to their electron deficiency.
Classification of Carbocations
Carbocations are classified as primary (1^o), secondary (2^o), or tertiary (3^o) based on the number of carbon atoms directly attached to the positively charged carbon.
Factors Affecting Carbocation Stability
Several factors influence carbocation stability:
Inductive effect
Hyperconjugative effect
Resonance effect
Steric effect
Aromatic system formation
Inductive Effect
Charge-dispersing factors stabilize ions.
Alkyl groups exert a +I (electron-releasing inductive) effect, partially neutralizing the positive charge on the carbocation.
This charge dispersion leads to stabilization.
Carbocation stability increases with the number of alkyl groups attached; for example, methyl groups in isopropyl cation stabilize the system through their +I effects.
Hyperconjugative Effect
Alkyl groups can reduce the positive charge via hyperconjugation.
The positive charge is dispersed over the α-hydrogens, stabilizing the system.
The stability of methyl-substituted carbocations increases with the number of α-hydrogens (hyperconjugative forms).
Resonance Effect
Resonance is a significant stabilizing factor.
Effective charge delocalization occurs when the positive carbon is adjacent to a double bond, leading to stabilization.
Allyl and benzyl cations are highly stabilized by resonance.
Steric Effect
Steric effects can enhance the stability of tertiary carbocations with bulky alkyl groups.
In tri-isopropyl cation, substituents are far apart, minimizing steric interference.
However, adding a nucleophile would change the hybridization from sp^2 to sp^3, pushing the isopropyl groups together, resulting in steric strain (B strain).
This steric hindrance makes the carbocation reluctant to react, increasing its stability.
Aromatic System Formation
The vacant p orbital of a carbocation can participate in forming a planar (4n + 2)π electron system, where n = 0, 1, 2….
Cycloheptatrienyl cation is unusually stable due to being a planar 6π electron aromatic system.
Reaction of Carbocations
Combination with an anion: Carbocations react with negatively charged species to form stable products (e.g., addition of hydrochloric acid to ethylene yielding ethyl chloride).
Elimination of a proton: Carbocations can donate a proton to form an unsaturated compound.
Structural Stability: Decrease in energy of transition state forms carbocation. The generated carbocation by unimolecular dissociation of leaving group is resonance stabilised.
Rearrangements
Intermolecular alkylation by carbocation can lead to polymerization reactions.
1,2-hydride shift: A 1-propyl cation rearranges to form a 2-propyl cation because the latter is more stable.
Allylic Rearrangements
Example:
S_N1 solvolysis of 3-chlorobut-1-ene.
Rapid nucleophilic attack occurs on C1 or C3.
Carbanions
Carbanions are species containing a negatively charged carbon atom.
The central carbon atom is sp^3 hybridized.
It is surrounded by three bonding pairs and one unshared pair of electrons in an sp^3 orbital, giving it a pyramidal shape.
Resonance-stabilized carbanions (e.g., allylic and benzylic) are sp^2 hybridized and have a trigonal planar structure.
Factors Affecting Carbanion Stability
The structural features responsible for carbanion stability include:
The amount of ‘s’ character of the carbanion carbon atom
Inductive electron withdrawal
Conjugation with an unsaturated system
Aromatic system formation
‘s’ Character of the Carbanion Carbon Atom
An electron pair in an orbital with large s character is more tightly held by the nucleus and has lower energy.
Carbanion stability increases with increasing ‘s’ character: sp > sp^2 > sp^3.
Inductive Electron Withdrawal
Groups with electron-withdrawing inductive effects (-I) stabilize carbanions by dispersing the negative charge.
For example, nitrogen ylides are stabilized by the -I effect of the adjacent positive nitrogen.
Conjugation with an Unsaturated System
Carbanions α to a double or triple bond are stabilized by delocalization of the negative charge with the π orbitals of the multiple bond.
Allylic, benzylic carbanions, and carbanions attached to functional groups like -NO_2, -C≡N, >C=O are stabilized by resonance.
Aromatic System Formation
The unshared pair of a carbanion can participate in a planar (4n + 2)π electron system, where n = 0, 1, 2….
Cyclopentadienyl anion is exceptionally stable due to being a 6π electron aromatic system.
Reaction of Carbanions
Displacement reaction: Alkylated product formed by displacement of halogen from an alkyl halide.
Addition to multiple bonds: Addition of Grignard's reagent to a carbonyl group.
Elimination reaction: Formation of alkene by alkyl halide in presence of alcoholic alkali.
Combination with cation
Rearrangements
Wittig rearrangement: Involves the formation of a carbanion stabilized by a substitution group R or R'.
Stevens Rearrangement: Uses a quaternary ammonium salt as the starting material.
The stability of the carbanion depends on the attached group, with electron-withdrawing groups (A) increasing stability.
Free Radicals
Homolytic cleavage of covalent bonds results in the formation of neutral species with unpaired electrons, known as free radicals.
Free radicals containing odd electrons on carbon atoms are called carbon radicals or simply free radicals (e.g., methyl radical (\dot{C}H_3), phenyl radical (Ph \cdot)).
Free radicals are classified as primary, secondary, and tertiary based on the number of carbon atoms directly attached to the carbon atom bearing the unpaired electron.
Stability of Free Radicals
Hyperconjugation: Free radicals are stabilized by hyperconjugation involving α-H atoms.
As the number of α-H atoms increases, hyperconjugation becomes more effective, and the radical becomes more stable.
The stability of simple alkyl radicals follows the order: tertiary (R3\dot{C}) > secondary (R2\dot{C}H) > primary (R\dot{C}H2) > methyl (\dot{C}H3).
Resonance: Resonance is a significant factor in stabilizing free radicals.
Effective delocalization of the unpaired electron with the π orbital system occurs when the carbon bearing the odd electron is α to a double bond.
Allyl and benzyl radicals are particularly stable due to resonance.
Steric Strain
Tertiary radicals gain stability from steric relief when a sp^2 hybridized radical is formed from a sp^3 hybridized precursor.
Repulsion between bulky alkyl groups is reduced by an increase in bond angles from 109.5^o to about 120^o.
Reactions of Free Radicals
Reactions of free radicals result in stable products (termination reactions) or lead to other radicals (propagation reactions).
Common termination reactions include simple combinations of similar or different radicals.
Another termination process is disproportionation.
Principal propagation reactions include:
Abstraction of another atom or group, usually a hydrogen atom.
Addition to a multiple bond: The radical formed may add to another double bond (vinyl polymerization).
Decomposition
Rearrangement
Aromaticity
Aromatic compounds are conjugated planar ring systems with delocalized π-electrons and alternating double and single bonds.
They exhibit high stability due to filled bonding molecular orbitals and greater resonance energy.
Aromatic compounds follow Hückel's rule: a cyclic planar conjugated species having (4n+2)π electrons (where n = 0, 1, 2, 3…) is aromatic.
Each carbon must be sp^2 or sp hybridized, and each atom in the ring must have an unhybridized p orbital.
Delocalization of π electrons over the ring lowers electronic energy and increases stability.
Diamagnetic ring current shifts protons outside the ring downfield and inner protons upfield in NMR spectra; such compounds are diatropic.
Features of Non-Aromatic Compounds
For a molecule to be non-aromatic, it must be:
Cyclic or acyclic
Lack a continuous and overlapping p-orbital system
Non-planar
Possess $4n π-electrons (where n = any integer)
Hückel's rule applies only to compounds with a continuous ring of overlapping p orbitals in a planar system. Cyclooctatetraene avoids π bond overlap by assuming a non-planar ‘tub-shaped’ conformation.
Features of Anti-Aromatic Compounds
For a molecule to be anti-aromatic, it must:
Be cyclic and planar
Have a continuous, overlapping ring of p orbitals.
Exhibit increased electronic energy and decreased stability upon π-electron delocalization.
Possess 4n π-electrons (where n = 1, 2, 3…).
Anti-aromatic systems exhibit a paramagnetic ring current, shifting outer protons upfield and inner protons downfield.
Types of Aromatic Compounds
For 2π electron systems:
Follow (4n+2)π electron system.
Aromatic if electrons are delocalized, non-aromatic if electrons are not delocalized.
For 4π electron systems:
Belong to $4nπ electron system.
Anti-aromatic if electrons are delocalized, non-aromatic if electrons are not delocalized.
For 6π electron systems:
Belong to (4n+2)π electron system.
Aromatic if electrons are delocalized, non-aromatic if electrons are not delocalized.
For 8π electron systems:
Belong to (4n)π electron system.
Anti-aromatic if electrons are delocalized, non-aromatic if electrons are not delocalized.
Homoaromatic Compounds
Conatin one or more sp^3-hybridized carbon atoms in a conjugate cyclic ring.
The sp^3-hybridized carbon atoms are out of the plane of the aromatic system allowing efective orbital overlapping in closed loop.
Homoaromatic compound involves delocalization of π- electron cloud bypassing sp^3 hybridized atom.
Quasi-Aromatic Compounds
Aromatic compounds where a +ve or -ve charge is part of Hückel's rule or aromaticity, with the charge present in the ring.
Stability and Energy Order
Stability Order: Aromatic > Homoaromatic > Non-aromatic > Anti-aromatic.
Energy Order: Anti-aromatic > Non-aromatic > Homoaromatic > Aromatic
Heterocycles
A heterocyclic compound is a cyclic compound that contains ring atom(s) other than carbon (N, O, S, P).
3-Membered Ring Heterocyclic Compounds
4-Membered Ring Heterocyclic Compounds
The Azete is an anti-aromatic compound.
In counting the number of π-electrons, you count the electrons which are delocalized over the ring.
In this case the nitrogen lone pair is localised and does not participate in resonance.
The nitrogen lone pair is in an sp^2 orbital which is orthogonal to the π system
So, the total number of π-electrons is only four: two from each double bond.
Five Membered Heterocycle: Pyrrole
Aromatic with 6π electrons
Sp^2 hybridised and planar
Lone pair is tied up in the aromatic ring
π-electron excessive; Electrophilic Aromatic Substitution is easy and Nucleophilic Substitution is difficult
Six Membered Heterocycle: Pyridine
Pyridine replaces the CH of benzene by a N atom (and a pair of electrons)
Hybridization = sp^2 with similar resonance stabilization energy
Lone pair of electrons not involved in aromaticity
Pyridine is a weak base
Pyridine is π-electron deficient; Electrophilic aromatic substitution is difficult and Nucleophilic aromatic substitution is easy
Fused Heterocyclic Compounds: Indole
Aromatic due to 10 π-electrons
Benzene part is non-reactive
Electrophilic aromatic substitution occurs at the 3- position
Organic Transformations for Making Useful Drugs
Aspirin (Acetyl Salicylic Acid)
Properties
Colourless / white crystalline solid, smells similar to vinegar.
Melting point of aspirin is 135 deg C, & decomposes at higher temperature.
Synthetic Route: The synthesis of aspirin is an esterification reaction.
Salicylic acid is treated with acetic anhydride, an acid derivative, causing a chemical reaction that turns OH group of salicylic acid into an ester group (R-OH → R- OCOCH3). This process yields aspirin and acetic acid. The catalyst used in this reaction is sulphuric acid or phosphoric acid.
Applications: Most commonly used as an anti-inflammatory and antipyretic.
Paracetamol
*Properties
* Melting point 169 °C (336 °F)
*Application
* Paracetamol is a common painkiller (analgesic) used to treat aches and pain.
* It can also be used to reduce a high temperature (antipyretic).
* Paracetamol's effects are thought to be related to inhibition of prostaglandin synthesis.
Dyes
Dyes are colored organic compounds used to impart color to various substances like fabrics, paper, food, hair, and drugs.
Dyes are soluble in water and/or an organic solvent, while pigments are insoluble in both.
Classification of Dyes
On the Basis of Source:
Natural dyes: derived from plants, invertebrates, or minerals.
Synthetic Dyes: Synthetic dyes are manufactured from organic molecules.
On the Basis of Chromophore:
Azo dyes: characterized by the presence of one or more azo groups —N = N—.
Triphenylmethane Dyes: have poor resistance to light and chemical bleaches.
Phthalein dyes: a class of dyes mainly used as pH indicators
Chemistry of Dyeing
Dyeing is applying color to fiber stock, yarn, or fabric with relatively permanent coloration.
Important determinants are coloration and absorption.
Coloration: Must be relatively permanent and not fade rapidly on exposure to light.
Absorption: Dye molecules concentrate on the fiber surface and are bound by:
Ionic forces
Hydrogen bonding
Van der Waals forces
Covalent chemical linkages
Exhaustion: In any dyeing process, heat must be supplied to the dye bath; energy is used in transferring dye molecules from the solution to the fiber as well as in swelling the fiber to render it more receptive.
Important Quality: evenness of dyeing, known as levelness is an important quality in the dyeing of all forms of natural and synthetic fibers.
Examples of Dyes
Methyl Orange
A pH indicator used in titrations.
Prepared from sulfanilic acid and N,N-dimethylaniline.
Indigotin
A distinctive blue dye known since prehistoric times, playing a key role in economies because of the rarity of natural blue dyes.
The chemical in indigo which is responsible for the blue colour is indigotin, which is a dark blue powder at room temperature and is insoluble in water and ethanol.